Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.
Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.
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DOI：
10.1016/s1473-3099(17)30171-8
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Möhrle JJ
中科院分区：
文献类型：
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作者：
McCarthy JS;Lotharius J;Rückle T;Chalon S;Phillips MA;Elliott S;Sekuloski S;Griffin P;Ng CL;Fidock DA;Marquart L;Williams NS;Gobeau N;Bebrevska L;Rosario M;Marsh K;Möhrle JJ
DSM 265是一种新型抗疟药，可抑制疟原虫二氢乳清酸脱氢酶（嘧啶生物合成所必需的酶）。我们研究了DSM 265的安全性、耐受性和药代动力学，并测试了其抗疟活性。年龄在18-55岁之间的健康受试者参加了一项两部分研究：第1部分，单次递增剂量（25-1200 mg）、双盲、随机化、安慰剂对照研究，以及第2部分，一项开放标签、随机化、活性对照药物对照研究，其中参与者接种恶性疟原虫诱导的血液期疟疾（IBSM）并用DSM 265（150 mg）或甲氟喹（10 mg/kg）治疗。主要终点是DSM 265安全性、耐受性和药代动力学。使用经验证的自动化系统创建随机化列表。两个部分均在澳大利亚新西兰临床试验注册中心注册，编号ACTRN 12613000522718（第1部分）和编号ACTRN 12613000527763（第2部分）。在第1部分中，73名受试者在2013年4月12日至2015年7月14日期间入组（DSM 265，n=55;安慰剂，n=18）。在第2部分中，9名受试者在2013年9月30日至11月25日期间入组（150 mg DSM 265，n=7; 10 mg/kg甲氟喹，n=2）。在第1部分中，报告了117起不良事件;未报告药物相关严重或重度事件。最常见的药物相关不良事件是头痛。平均DSM 265血浆峰浓度（Cmax）范围为1310 ng/mL至34 800 ng/mL，达到Cmax的中位时间（tmax）为1.5 h至4 h，平均消除半衰期为86 h至118 h。 在第2部分中，DSM 265（150 mg）组48 h时的log 10寄生虫减少率为1·55（95% CI 1.42 - 1.67）和甲氟喹（10 mg/kg）组为2.34（2.17 - 2.52），相应的寄生虫清除半衰期分别为9.4 h（8.7 - 10.2）和6.2 h（5.7 - 6.7）。血液中DSM 265的中位最小抑制浓度估计为1040 ng/mL（范围552-1500），导致预测的单次有效剂量为340 mg。接受甲氟喹的参与者的寄生虫清除明显快于接受DSM 265的参与者（p<0.0001）。DSM 265的良好安全性、长消除半衰期和抗疟作用支持其作为单剂量抗疟联合治疗中的伙伴药物的发展。惠康信托基金、英国国际发展部、全球卫生创新技术基金、比尔和梅林达·盖茨基金会。
DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Healthy participants aged 18–55 years were enrolled in a two-part study: part 1, a single ascending dose (25–1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42–1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17–2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7–10·2) and 6·2 h (5·7–6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552–1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001). The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.
新型抗疟疾组合疗法的最佳剂量发现。
DOI：
10.1111/j.1365-3156.2012.02963.x
发表时间：
2012-04
期刊：
Tropical medicine & international health : TM & IH
影响因子：
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作者：
Duparc S;Lanza C;Ubben D;Borghini-Fuhrer I;Kellam L
通讯作者：
Kellam L